Details for Patent: 6,797,709

An aromatic nitrogen-containing 6-membered cyclic compound of the formula (I): ##STR1## wherein Ring A is a substituted or unsubstituted nitrogen-containing heterocyclic group; R.sup.1 is a substituted or unsubstituted lower alkyl group, --NH--Q--R.sup.3 (R.sup.3 is a substituted or unsubstituted nitrogen containing heterocyclic group, and Q is a lower alkylene group or a single bond), or --NH--R.sup.4 (R.sup.4 is a substituted or unsubstituted cycloalkyl group); R.sup.2 is a substituted or unsubstituted aryl group; one of Y and Z is .dbd.CH--, and the other is .dbd.N--, or a pharmaceutically acceptable salt thereof, these compounds exhibiting excellent selective PDE V inhibitory activities, and hence, being useful in the prophylaxis or treatment of penile erectile dysfunction, etc.

wherein Ring A is a substituted or unsubstituted nitrogen-containing heterocyclic group; R.sup.1 is a substituted or unsubstituted lower alkyl group, a group of the formula: --NH--Q--R.sup.3 in which R.sup.3 is a substituted or unsubstituted nitrogen containing heterocyclic group, and Q is a lower alkylene group or a single bond, or a group of the formula: --NH--R.sup.4 in which R.sup.4 is a substituted or unsubstituted cycloalkyl group; R.sup.2 is a substituted or unsubstituted aryl group; Y is a group of the formula: .dbd.CH--, and Z is a group of the formula: .dbd.N--, or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1, wherein the nitrogen-containing heterocyclic group of the "substituted or unsubstituted nitrogen-containing heterocyclic group" for Ring A is a 5- or 6-membered nitrogen-containing heteromonocyclic group or a 8- to 10-membered nitrogen-containing heterobicyclic group, and the substituent of the above "substituted or unsubstituted nitrogen-containing heterocyclic group" is selected from the group consisting of (1) a lower alkyl group, (2) a hydroxy-substituted lower alkyl group, (3) a formyl group, (4) an oxo group, (5) an amino group, (6) a hydroxy group, (7) a lower alkoxycarbonyl group, and (8) a pyrimidinyl group substituted by (i) a benzylamino group substituted by a halogen atom and a lower alkoxy group, and (ii) a cycloalkylcarbamoyl group substituted by a hydroxy group, R.sup.1 is a lower alkyl group which may optionally be substituted by a group selected from the group consisting of a lower alkoxy group, a hydroxy group, a morpholinyl group, a lower alkylsulfonyl group, a di-(lower alkyl)phosphino group, a di-(lower alkyl)amino group, a pyrimidinyl-substituted lower alkylamino group, a pyridyl group, a pyridylamino group and a lower alkyl-substituted piperazinyl group, a group of the formula: --NH--Q--R.sup.3, or a group of the formula: --NH--R.sup.4, the nitrogen-containing heterocyclic group of the "substituted or unsubstituted nitrogen-containing heterocyclic group" for R.sup.3 is a 5- or 6-membered nitrogen-containing heteromonocyclic group or a 8- to 10-membered nitrogen-containing heterobicyclic group, and the substituent of the above "substituted or unsubstituted nitrogen-containing heterocyclic group" is selected from the group consisting of a lower alkyl group, a hydroxy-substituted lower alkyl group, an oxo group, an amino group, a di-(lower alkyl)amino group, a lower alkanoyl group and a cyano-substituted lower alkyl group, R.sup.4 is a cycloalkyl group being substituted by a group selected from the group consisting of hydroxy group, a lower alkoxy group and a pyrimidinyloxy group, R.sup.2 is a phenyl group being substituted by a group selected from the group consisting of a lower alkoxy group, a halogen atom, a cyano group, a nitro group, a hydroxy group and a lower alkyl group.

3. The compound according to claim 2, wherein the nitrogen-containing heterocyclic group of the substituted or unsubstituted nitrogen-containing heterocyclic group for Ring A is a 5- or 6-membered nitrogen-containing heteromonocyclic group of the formula: ##STR365##

or a nitrogen-containing heterobicyclic group of the following formula wherein the above-mentioned 5- or 6-membered nitrogen-containing heteromonocyclic group and a 5- or 6-membered cyclic group are fused: ##STR366##

and the nitrogen-containing heterocyclic group of the substituted or unsubstituted nitrogen-containing heterocyclic group for R.sup.3 is a non-aromatic nitrogen-containing heteromonocyclic group of the formula: ##STR367##

or an aromatic nitrogen-containing heterocyclic group of the formula: ##STR368##

4. The compound according to claim 1, wherein the nitrogen-containing heterocyclic group of the "substituted or unsubstituted nitrogen-containing heterocyclic group" for Ring A is a 5- or 6-membered nitrogen-containing heteromonocyclic group or a 8- to 10-membered nitrogen-containing heterobicyclic group, and the substituent of the above "substituted or unsubstituted nitrogen-containing heterocyclic group" is selected from the group consisting of a lower alkyl group, a hydroxy-substituted lower alkyl group, a formyl group and an oxo group, R.sup.1 is a lower alkyl group which may optionally be substituted by a group selected from the group consisting of a lower alkoxy group and a morpholinyl group, a group of the formula: --NH--Q--R.sup.3, or a group of the formula: --NH--R.sup.4, the "substituted or unsubstituted nitrogen-containing heterocyclic group" for R.sup.3 is a 5- or 6-membered nitrogen-containing heteromonocyclic group which may optionally be substituted by a lower alkyl group, R.sup.4 is a cycloalkyl group being substituted by a group selected from the group consisting of hydroxy group and a lower alkoxy group, R.sup.2 is a phenyl group being substituted by a group selected from the group consisting of a lower alkoxy group, a halogen atom and a cyano group.

5. The compound according to claim 4, wherein the nitrogen-containing heterocyclic group of the "substituted or unsubstituted nitrogen-containing heterocyclic group" for Ring A is a 5- or 6-membered non-aromatic nitrogen-containing heteromonocyclic group of the formula: ##STR369##

or a nitrogen-containing heterobicyclic group of the following formula wherein the above-mentioned 5- or 6-membered non-aromatic nitrogen-containing heteromonocyclic group and a 5- or 6-membered aromatic nitrogen-containing heteromonocyclic group are fused: ##STR370##

the nitrogen-containing heterocyclic group of the "substituted or unsubstituted nitrogen-containing heterocyclic group" for R.sup.3 is a non-aromatic nitrogen-containing heteromonocyclic group of the formula: ##STR371##

or an aromatic nitrogen-containing heteromonocyclic group of the formula: ##STR372##

6. The compound according to claim 1, wherein Ring A is a group of the formula: ##STR373##

R.sup.1 is a lower alkyl group, a lower alkoxy-substituted lower alkyl group, a morpholinyl-substituted lower alkyl group, a group of the formula: --NH--Q--R.sup.3, or a group of the formula: --NH--R.sup.4, R.sup.3 is a group of the formula: ##STR374##

R.sup.4 is a group of the formula: ##STR375##

and R.sup.2 is a group of the formula: ##STR376##

7. The compound according to claim 1, wherein the nitrogen-containing heterocyclic group of the "substituted or unsubstituted nitrogen-containing heterocyclic group" for Ring A is a 5- or 6-membered nitrogen-containing heteromonocyclic group or a 8- to 10-membered nitrogen-containing heterobicyclic group, and the substituent of the above "substituted or unsubstituted nitrogen-containing heterocyclic group" is a group selected from the group consisting of a lower alkyl group, a hydroxy-substituted lower alkyl group, a formyl group and an oxo group, R.sup.1 is a lower alkoxy-substituted lower alkyl group, a group of the formula: --NH--Q--R.sup.3, or a group of the formula: --NH--R.sup.4, the "substituted or unsubstituted nitrogen-containing heterocyclic group" for R.sup.3 is a 5- or 6-membered nitrogen-containing heteromonocyclic group which may optionally be substituted by a lower alkyl group, R.sup.4 is a hydroxy-substituted cycloalkyl group, and R.sup.2 is a phenyl group being substituted by a group selected from the group consisting of a lower alkoxy group and a halogen atom.

8. The compound according to claim 7, wherein the nitrogen-containing heterocyclic group of the "substituted or unsubstituted nitrogen-containing heterocyclic group" for Ring A is a 5- or 6-membered non-aromatic nitrogen-containing heteromonocyclic group of the formula: ##STR377##

a group of the formula: ##STR378##

the nitrogen-containing heterocyclic group of the "substituted or unsubstituted nitrogen-containing heterocyclic group" for R.sup.3 is a non-aromatic nitrogen-containing heteromonocyclic group of the formula: ##STR379##

or an aromatic nitrogen-containing heteromonocyclic group of the formula: ##STR380##

9. The compound according to claim 1, wherein Ring A is a group of the formula: ##STR381##

R.sup.1 is a lower alkoxy-substituted lower alkyl group, a group of the formula: --NH--Q--R.sup.3, or a group of the formula: --NH--R.sup.4, R.sup.3 is a group of the formula: ##STR382##

R.sup.4 is a group of the formula: ##STR383##

and R.sup.2 is a group of the formula: ##STR384##

10. The compound according to claim 1, wherein the nitrogen-containing heterocyclic group of the "substituted or unsubstituted nitrogen-containing heterocyclic group" for Ring A is a 5- or 6-membered nitrogen-containing heteromonocyclic group or a 8- to 10-membered nitrogen-containing heterobicyclic group, and the substituent of the above "substituted or unsubstituted nitrogen-containing heterocyclic group" is a hydroxy-substituted lower alkyl group, R.sup.1 is a group of the formula: --NH--Q--R.sup.3, the "substituted or unsubstituted nitrogen-containing heterocyclic group" for R.sup.3 is a 5- or 6-membered nitrogen-containing heteromonocyclic group which may optionally be substituted by a lower alkyl group, and R.sup.2 is a phenyl group being substituted by a group selected from the group consisting of a lower alkoxy group and a halogen atom.

11. The compound according to claim 10, wherein the nitrogen-containing heterocyclic group of the "substituted or unsubstituted nitrogen-containing heterocyclic group" for Ring A is a 5- or 6-membered non-aromatic nitrogen-containing heteromonocyclic group of the formula: ##STR385##

or a group of the formula: ##STR386##

the nitrogen-containing heterocyclic group of the "substituted or unsubstituted nitrogen-containing heterocyclic group" for R.sup.3 is a non-aromatic nitrogen-containing heteromonocyclic group of the formula: ##STR387##

or an aromatic nitrogen-containing heteromonocyclic group of the formula: ##STR388##

12. The compound according to claim 1, wherein Ring A is a group of the formula: ##STR389##

R.sup.1 is a group of the formula: --NH--Q--R.sup.3, R.sup.3 is a group of the formula: ##STR390##

and

R.sup.2 is a group of the formula: ##STR391##

13. The compound according to claim 1, wherein said compound is selected from the group consisting of: (S)-2-[N-(2-pyrimidinylmethyl)carbamoyl]-3-(3-chloro-4-methoxybenzylamino)- 5-[2-hydroxymethyl-1-pyrrolidinyl]pyrazine; (S)-2-[N-(2-morpholinoethyl)carbamoyl]-3-(3-chloro-4-methoxybenzylamino)-5- (2-hydroxymethyl-1-pyrrolidinyl)pyrazine; and 2-[N-(2-pyrimidinylmethyl)carbamoyl]-3-(3-chloro-4-methoxybenzylamino)-5-(5 ,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-7-yl)pyrazine; or a pharmaceutically acceptable salt thereof.

14. The compound according to claim 13, wherein the compound is (S)-2-[N-(2-pyrimidinylmethyl)carbamoyl]-3-(3-chloro-4-methoxybenzylamino)- 5-[2-hydroxymethyl-1-pyrrolidinyl]pyrazine, or a pharmaceutically acceptable salt thereof.

15. The compound of claim 13, wherein the compound is (S)-2-[N-(2-morpholinoethyl)carbamoyl]-3-(3-chloro-4-methoxybenzylamino)-5- (2-hydroxymethyl-1-pyrrolidinyl)pyrazine.

16. A pharmaceutical composition, which contains as an active ingredient the compound as set forth in any one of claims 1-12 and 13-15 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier therefor.

17. A method for treatment of penile erectile dysfunction, which comprises administering to a patient in need thereof an effective amount of the compound as set forth in any one of claims 1-12 and 13-15, or a pharmaceutically acceptable salt thereof.

18. A method for treatment of pulmonary hypertension, which comprises administering to a patient in need thereof an effective amount of the compound as set forth in any one of claims 1-12 and 13-15 or a pharmaceutically acceptable salt thereof.

19. A method for treatment of diabetic gastroparesis, which comprises administering to a patient in need thereof an effective amount of the compound as set forth in any one of claims 1-12 and 13-15, or a pharmaceutically acceptable salt thereof.

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